Skip to main content
Log in

Small genomic rearrangements involving FMR1 support the importance of its gene dosage for normal neurocognitive function

  • Short Communication
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Fragile X syndrome, the most common form of X-linked intellectual disability, results from transcriptional silencing of the FMR1 gene. As of yet, the phenotypic consequences of the duplication of FMR1 have not been well characterized. In this report, we characterize the clinical features in two females with duplications involving only the FMR1 gene. In addition, we describe the phenotypes of two subjects with deletion of FMR1 and show that both loss and gain of FMR1 copy number can lead to overlapping neurodevelopmental phenotypes. Our report supports the notion that FMR1 gene dosage is important for normal neurocognitive function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Hagerman PJ (2008) The fragile X prevalence paradox. J Med Genet 45:498–499

    Article  PubMed  Google Scholar 

  2. Hammond LS, Macias MM, Tarleton JC, Shashidhar Pai G (1997) Fragile X syndrome and deletions in FMR1: new case and review of the literature. Am J Med Genet 72:430–434

    Article  PubMed  CAS  Google Scholar 

  3. Meijer H, de Graaff E, Merckx DM, Jongbloed RJ, de Die-Smulders CE et al (1994) A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum Mol Genet 3:615–620

    Article  PubMed  CAS  Google Scholar 

  4. de Graaff E, Rouillard P, Willems PJ, Smits AP, Rousseau F et al (1995) Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients. Hum Mol Genet 4:45–49

    Article  PubMed  Google Scholar 

  5. Petek E, Kroisel PM, Schuster M, Zierler H, Wagner K (1999) Mosaicism in a fragile X male including a de novo deletion in the FMR1 gene. Am J Med Genet 84:229–232

    Article  PubMed  CAS  Google Scholar 

  6. Garcia Arocena D, de Diego Y, Oostra BA, Willemsen R, Mirta Rodriguez M (2000) A fragile X case with an amplification/deletion mosaic pattern. Hum Genet 106:366–369

    Article  PubMed  CAS  Google Scholar 

  7. Han XD, Powell BR, Phalin JL, Chehab FF (2006) Mosaicism for a full mutation, premutation, and deletion of the CGG repeats results in 22% FMRP and elevated FMR1 mRNA levels in a high-functioning fragile X male. Am J Med Genet A 140:1463–1471

    PubMed  Google Scholar 

  8. Trottier Y, Imbert G, Poustka A, Fryns JP, Mandel JL (1994) Male with typical fragile X phenotype is deleted for part of the FMR1 gene and for about 100 kb of upstream region. Am J Med Genet 51:454–457

    Article  PubMed  CAS  Google Scholar 

  9. Gu Y, Lugenbeel KA, Vockley JG, Grody WW, Nelson DL (1994) A de novo deletion in FMR1 in a patient with developmental delay. Hum Mol Genet 3:1705–1706

    Article  PubMed  CAS  Google Scholar 

  10. Hirst M, Grewal P, Flannery A, Slatter R, Maher E et al (1995) Two new cases of FMR1 deletion associated with mental impairment. Am J Hum Genet 56:67–74

    PubMed  CAS  Google Scholar 

  11. Wolff DJ, Gustashaw KM, Zurcher V, Ko L, White W et al (1997) Deletions in Xq26.3–q27.3 including FMR1 result in a severe phenotype in a male and variable phenotypes in females depending upon the X inactivation pattern. Hum Genet 100:256–261

    Article  PubMed  CAS  Google Scholar 

  12. Fengler S, Fuchs S, Konig R, Arnemann J (2002) Mosaicism for FMR1 and FMR2 deletion: a new case. J Med Genet 39:200–201

    Article  PubMed  CAS  Google Scholar 

  13. Probst FJ, Roeder ER, Enciso VB, Ou Z, Cooper ML et al (2007) Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation. Am J Med Genet A 143A:1358–1365

    Article  PubMed  CAS  Google Scholar 

  14. Yachelevich N, Gittler JK, Klugman S, Feldman B, Martin J et al. (2011) Terminal deletions of the long arm of chromosome X that include the FMR1 gene in female patients: a case series. Am J Med Genet A 155A:870-874

    Google Scholar 

  15. Rio M, Malan V, Boissel S, Toutain A, Royer G et al (2011) Familial interstitial Xq27.3q28 duplication encompassing the FMR1 gene but not the MECP2 gene causes a new syndromic mental retardation condition. Eur J Hum Genet 18:285–290

    Article  Google Scholar 

  16. Vengoechea J., Parikh AS, Zhang S, Tassone F (2012) De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity. Eur J Hum Genet. doi:10.1038/ejhg.2012.78

  17. El-Hattab AW, Smolarek TA, Walker ME, Schorry EK, Immken LL et al (2009) Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping. Hum Genet 126:589–602

    Article  PubMed  Google Scholar 

  18. Ou Z, Kang SH, Shaw CA, Carmack CE, White LD et al (2008) Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses. Genet Med 10:278–289

    Article  PubMed  CAS  Google Scholar 

  19. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51:1229–1239

    PubMed  CAS  Google Scholar 

  20. Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107:343–349

    Article  PubMed  CAS  Google Scholar 

  21. Ramocki MB, Zoghbi HY (2008) Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455:912–918

    Article  PubMed  CAS  Google Scholar 

  22. Hessl D, Rivera SM, Reiss AL (2004) The neuroanatomy and neuroendocrinology of fragile X syndrome. Ment Retard Dev Disabil Res Rev 10:17–24

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families for their kind cooperation. This work was supported in part by fellowship grants by the National Urea Cycle Disorders Foundation and LCRC from Osteogenesis Imperfecta Foundation (SNSC), DK081735-01A1, NIH /NIGMS T32 contract grant no. GM07526 (AE).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sau Wai Cheung.

Additional information

Sandesh CS Nagamani and Ayelet Erez contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagamani, S.C.S., Erez, A., Probst, F.J. et al. Small genomic rearrangements involving FMR1 support the importance of its gene dosage for normal neurocognitive function. Neurogenetics 13, 333–339 (2012). https://doi.org/10.1007/s10048-012-0340-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-012-0340-y

Keywords

Navigation